The transdermal administration of drugs is becoming increasingly accepted as a preferred mode of delivery.
Transdermal delivery of drugs provides many advantages over conventional oral administration. Advantages of transdermal systems include convenience, noninterrupted therapy, improved patient compliance, reversibility of treatment (by removal of the system from the skin), elimination of "hepatic first pass" effect, the high degree of control over blood concentration of any particular drug and consequent reduction of side effects.
Although transdermal systems have many advantages, most drugs are not amenable to this mode of administration due to the well known barrier properties of the skin. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. The molecule must then penetrate the viable epidermis, the papillary dermis, and then the capillary walls and into systemic circulation. Along the way, each of the above mentioned tissues will exhibit a different resistance to penetration by the same molecule. However, it is the stratum corneum that presents the greatest barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum, the outer horny layer of the skin, is a complex structure of compact keratinized cell remnants separated by lipid domains. Compared to the oral or gastric mucosa, the stratum corneum is much less permeable to outside molecules.
The flux of a drug across the skin can be increased by changing either a) the resistance (the diffusion coefficient), or b) the driving force (the solubility of the drug in the stratum corneum and consequently the gradient for diffusion). Many enhancer compositions have been developed to change one or more of these factors, and are known in the art. U.S. Pat. Nos. 4,006,218, 3,551,154 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of topically applied drugs through the stratum corneum. Combinations of enhancers consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermal delivery of steroids such as progestogens and estrogens. A dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720. U.S. Pat. No. 5,006,342 lists numerous enhancers for transdermal drug administration consisting of fatty acid esters or fatty alcohol ethers of C.sub.2 to C.sub.4 alkanediols, where each fatty acid/alcohol portion of the ester/ether is of about 8 to 22 carbon atoms. U.S. Pat. No. 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C.sub.2 or C.sub.3 alkanol and an inert diluent such as water.
The use of sorbitan esters of long chain aliphatic acids as skin permeation enhancers is disclosed in U.S. Pat. Nos. 5,122,383; 5,212,199 and 5,227,169. Skin permeation enhancement using aliphatic alcohol esters of lactic acid is disclosed in U.S. Pat. No. 5,154,122, World Patent 95/09006 and in Dohi et al., Enhancing Effects of Myristyl Lactate and Lauryl Lactate on Percutaneous Absorption of Indomethacin, Chem Pharm. Bull. 38 (October 1990) 2877-2879. U.S. Pat. No. 5,314,694 also makes reference to the use of esters of fatty acid alcohols, i.e. lauryl alcohol and lactic acid as a permeation enhancer component.
World Patent 96/37231 teaches the use of acyl lactylates as permeation enhancers for drug delivery purposes. This patent is specific to esters of fatty acids and lactic acid such as caproyl lactylic acid and lauroyl lactylic acid. It is stated that the salt form of acyl lactylates are not effective as permeation enhancers.
Skin permeation enhancement due to fatty acid sucrose esters is disclosed in U.S. Pat. No. 4,940,586. Penetration enhancement resulting from combining free base and acid addition salt combinations of drugs is taught in U.S. Pat. No. 4,888,354. Enhancement of drugs by means of subsaturation in a carrier is disclosed in U.S. Pat. No. 5,164,190.
Occlusive adhesive devices, i.e. patches, for transdermal delivery of drugs is taught in U.S. Pat. Nos. 4,849,224; 4,983,395; 5,152,997 and 5,302,395. These patches are in reservoir or matrix forms as will be more fully characterized in the detailed description below.
Many of the enhancer systems possess negative side effects such as toxicity, skin irritation and incompatibility with the drugs or other ingredients making up the transdermal system.
U.S. Pat. No. 4,855,294 discloses compositions for reducing skin irritation caused by drug/enhancer compositions having skin irritation properties comprising a percutaneously absorbable drug, a binary enhancer composition consisting of a solvent and a cell envelope disordering compound, combined with an amount of glycerin sufficient to provide an anti-irritating effect.
It would be desirable to have an enhancer composition which not only enabled the passage of drug compositions across the skin barrier but which was also beneficial to the moisturization, stability and overall vitality of the epidermis. Skin having properly moisturized stratum corneum is smooth to the touch, flexible and elastic due to the presence of sufficient bound water. A 1% variation of water content may be enough to modify skin elasticity and permeability. Suitable skin hydration also promotes transdermal delivery of drugs through the stratum corneum.
Fatty acid lactylates and glycolates are known to be used as hair conditioners as shown by U.S. Pat. No. 3,728,447. Further, fatty acid lactylates and their salts, prepared from C.sub.6 to C.sub.22 fatty acids, are known to be used in cosmetics and have the ability to complex with skin proteins. See Murphy, et al., Acyl Lactylates in Cosmetics, D&CI (May, 1978) 35 ff and Murphy, et al., Sorption of acyl lactylates by hair and skin as documented by radio tracer studies, Cosmetics & Toiletries, 94 (March 1979) 43-49. Combinations of acyl lactylates or glycolates with soaps or synthetic detergents in skin conditioning toilet bars is the subject of U.S. Pat. No. 4,198,311. The use of a salt of a fatty acid ester of lactylic acid as one of many components in a shaving cream formulation is taught in U.S. Pat. No. 4,761,279.
Lanolinyl lactylates, are shown in U.S. Pat. No. 4,422,952 to be used in water-in-oil emulsions as cosmetic supports or pharmaceutical excipients, e.g. to be used in ointments, balms, creams and the like. No physiological effect is attributed to these esters.
U.S. Pat. No. 4,822,601 is drawn to cosmetic base compositions exhibiting therapeutic properties including sucrose fatty acid esters and fatty acid lactylates, with or without shea butter. Following application to the skin, a thickening of the epidermal layer was noted indicating a healthier and less dry skin. It was noted that topical application of such compositions also demonstrated enhanced wound healing properties and decreased sensitivity to UV light.
Extensive summaries of the prior art for acyl lactylates and of the properties of such for cosmetic use are found in U.S. Pat. No. 5,427,772 and World Patent 96/37231.
In none of the above is the use of fatty acid esters of glycolic acid and its salts as permeation enhancers for active pharmaceutical agents taught, suggested or demonstrated.